Platelet-rich fibrin-derived extracellular vesicles: emerging biological mediators in periodontal regeneration

Platelet-rich fibrin (PRF) is an autologous biomaterial increasingly used in periodontal regeneration due to its ability to release bioactive molecules in a sustained manner. Recent research indicates that extracellular vesicles (EVs) released during PRF clot formation may serve as pivotal paracrine mediators, orchestrating immune modulation and tissue healing. This review provides a comprehensive overview of the biogenesis, molecular cargo, immunomodulatory activity, and regenerative potential of PRF-derived extracellular vesicles (PRF-EVs), with emphasis on their translational relevance in periodontal therapy. A narrative analysis was conducted using PubMed, Scopus, and Web of Science databases (2018-2025). Studies investigating EV isolation, characterization, immunoregulatory mechanisms, and regenerative applications related to PRF or platelet-derived EVs were critically evaluated in accordance with the MISEV2023 guidelines. PRF-EVs encapsulate growth factors (TGF-β1, VEGF, PDGF-A), matrix-regulating proteins (MMP-9, thrombospondin-1), and regulatory microRNAs (miR-21, miR-146a). These vesicles promote macrophage polarization toward the M2 phenotype, suppress NF-κB activation, rebalance the Th17/Treg axis, and enhance fibroblast migration, angiogenesis, and osteogenesis. Comparative analyses reveal that while mesenchymal stem cell-derived EVs exhibit higher bioengineering potential, PRF-EVs exhibit promising biosafety and clinical feasibility; however, existing human trials remain limited in scale and duration, and long-term safety data are still required. Integration with hydrogels or 3D-printed scaffolds further enables controlled release and targeted local action. PRF-EVs constitute a cell-free, autologous, and biologically active platform that bridges immune regulation and regenerative healing. Future studies should focus on standardizing isolation and dosing protocols, applying AI-assisted quality control, and conducting multicenter clinical trials to ensure reproducibility and translational reliability in periodontal regeneration. These findings provide a biological and technological rationale supporting the potential application of PRF-EVs in evidence-based periodontal regenerative therapy.